Genetic Variant HFM1:p.Ser1178Cys (chr1-91276683-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001017975.6(HFM1):c.3533C>G(p.Ser1178Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000115 in 1,568,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

Publications

1 publications found

Variant links:

Genes affected

HFM1 (HGNC:20193): (helicase for meiosis 1) The protein encoded by this gene is thought to be an ATP-dependent DNA helicase and is expressed mainly in germ-line cells. Defects in this gene are a cause of premature ovarian failure 9 (POF9). [provided by RefSeq, Apr 2014]

HFM1 Gene-Disease associations (from GenCC):

premature ovarian failure 9
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

HFM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17955601).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFM1	NM_001017975.6	MANE Select	c.3533C>G	p.Ser1178Cys	missense	Exon 32 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.3123C>G		non_coding_transcript_exon	Exon 26 of 33

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HFM1	ENST00000370425.8	TSL:1 MANE Select	c.3533C>G	p.Ser1178Cys	missense	Exon 32 of 39	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1	TSL:1	c.1166C>G	p.Ser389Cys	missense	Exon 13 of 19	ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5	TSL:2	n.1459C>G		non_coding_transcript_exon	Exon 15 of 21

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000138

AC:

AN:

217026

AF XY:

0.0000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000918

AC:

AN:

1416356

Hom.:

Cov.:

AF XY:

0.00000852

AC XY:

AN XY:

704404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30874

American (AMR)

AF:

0.00

AC:

AN:

33064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24734

East Asian (EAS)

AF:

0.000132

AC:

AN:

37864

South Asian (SAS)

AF:

0.00

AC:

AN:

77420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095622

Other (OTH)

AF:

0.000137

AC:

AN:

58412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41524

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.018

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.3

PhyloP100

4.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.026

Polyphen

0.99

Vest4

0.43

MutPred

0.52

Loss of disorder (P = 0.0133)

MVP

0.46

MPC

0.27

ClinPred

0.84

GERP RS

4.5

Varity_R

0.16

gMVP

0.15

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over